2,6 - bis-trifluoromethyl-phenyl - 4 - pyridinecarboxylic acid and derivatives thereof

ABSTRACT

A SERIES OF TRIFLUOROMETHYL SUBSTITUTED-2,6-DIPHENYL-4PYRIDYLCARBINOLAMINES IS HEREIN DISCLOSED WHICH HAS VALUE IN TREATMENT OF PLASMODIAL INFECTIONS. THE COMPOUNDS HAVE SUBSTITUTED PHENYL GROUPS AT POSITIONS 2- AND 6- ON THE PYRIDINE MOIETY, WITH THE ELECTRONEGATIVE SUBSTITUENTS (THE SAME, OR DIFFERENT) PRESENT ON THE PHENYL NUCLEI AT LEAST ONE OF WHICH IS TRIFLUOROMETHYL. THE SYNTHESES OF SUCH SERIES IS DESCRIBED, TOGETHER WITH A METHOD FOR SEPARATION OF RACEMATES OF A REPRESENTATIVE 4-PYRIYLCAR BINOLAMINE TYPE.

United States Patent 2,6 BIS-TRIFLUOROMETHYL-PHENYL 4 PYRI- DINECARBOXYLIC ACID AND DERIVATIVES THEREOF Arthur B. Ash, 1519 Chateaufont Place, Detroit, Mich. 48207; Peter Blumbergs, 22021 Sunset, Oak Park, Mich. 48237; Anica Markovac, 18271 Meadowood, Lathrup Village, Mich. 48075; and Maurice P. La Montague, 3539 Cero Drive, Sterling Heights, Mich. 48077 No Drawing.'0riginal application June 7, 1971, Ser. No. 150,746. Divided and this application July 31, 1972, Ser. No. 276,685

Int. Cl. C07d 31/36 US. Cl. 260-295 R 3 Claims ABSTRACT OF THE DISCLOSURE A series of trifluoromethyl substituted-2,6-diphenyl-4- pyridylcarbinolamines is herein disclosed which has value in treatment of plasmodial infections. The compounds have substituted phenyl groups at positions 2- and 6- on the pyridine moiety, with the electronegative substituents (the same, or different) present on the phenyl nuclei at least one of which is trifiuoromethyl. The syntheses of such series is described, together with a method for separation of racemates of a representative 4-pyn'dylcarbinolamine type.

This application is a divisional of our earlier application Ser. No. 150,746, filed June 7, 1971.

BACKGROUND OF THE INVENTION The subject invention relates to trifluoromethyl substituted-Z,6-diphenyl-4-pyridinecarbinolamines having enhanced antimalarial activity, and to means for achieving the snythesis of such compounds. Specifically, the new products are pyridine-4-carbinols bearing a basic function in the alpha-position, and having the same or different substituted-phenyl groupings at positions 2- and 6- on the pyridine moiety at least one of the substituents being trifluoromethyl. This type of compound is shown as Structure I. For convenience in administration as well as stability under storage, it is preferred that subject bases be transformed into acid-addition salts with pharmaceutically acceptable inorganic or organic acids.

Prior investigations have demonstrated that certain allied apha-di(lower alkyl) aminomethyl-2,6-diphenyl 4- pyridinecarbinols have antimalarial activity. The present invention relates to representatives which dilfer structurally from those known hitherto, and provide advantages in chemotherapeutic index and also in potential for avoiding unwanted side-effects such as phototoxicity.

DETAILED DISCLOSURE OF THE INVENTION moreover.

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The above (Structure I) establishes the new antimalarial agents as pyridine-4-carbinols bearing a basically-substituted unit in the alpha-position, and the same or different subsituted-phenyl groupings on the pyridine ring system. This comes from definition of terms, wherein,

R=hydrogen, while R hydrogen or (lower-alkyl), and

R (lower alkyl), the same or different from R or X is selected from trifiuoromethyl and mono or difiuoro, chloro or bromo wherein X is in the 3, 4 or 3 and 4 positions and wherein CF is in the 3 or 4 position. The term lower alkyl as used herein means 1 to 10 carbon atoms which can be straight, branched chain or cyclic with repeating methylene groups.

The patterns of worth for representatives of Structure I have been established through use of highly standardized tests in experimental mammals. The preferred mode for administering these compounds consists in use of nontoxic acid-addition salts, inclusive of those formed from (I) and acids such as hydrochloric, hydrobromic, sulfamic, sulfuric, malic, fumaric, beta-resorcylic, or pamoic acid. Said salts may be administered orally in the form of tablets, capsules, or drages when admixed with solid excipients such as lactose, sucrose, starch, microcrystalline cellulose, magnesium stearate, or talc. The foregoing compositions are preferred means for oral administration over use of flavored syrups or tinctures containing the antimalarial drug. Under special circumstances, parenteral administration may be indicated, employing an aqueous solution of the agent or an oleaginous formulation of it. Aqueous solutions could be prepared in water, physiological saline, Ringers solution, or the like, either with or without buffers. Oleaginous formulations may be made in natural oils (as peanut oil or olive oil), or in benzyl benzoate, for example. The several possible isomeric forms for Structure I are to be included among the preferred antimalarials, and advantage may accrue in the choice of one or other of these.

This invention includes mode for the chemical synthesis of the series defined by Structure I. R represents an extension and amplification of art which certain of the present inventors have divulged in copending patent application of Ser. No. 784,467 filed Dec. 17, 1968 on Antimalarial Compounds and Process for the Preparation Thereof and also an application entitled 4-Pyridylcarbinolamine Antimalarials filed on even date with the present application. Charts -1 through 3 have been used to outline the synthesis of the subject carbinolamines. As is apparent from the structure, such series occur in optically active form. A representative type, where two optical centers are present, has been separated into a pair of racemates, one of which has appreciable antimalarial activity. In another case, where only one optical center is present, the racemic pair resulting from synthesis, was subsequently separated into the dextrorotatory and laevorotatory forms with resulting significant antimalarial differences.

The course of synthesis of alpha-(dialkylaminomethyl)- 2,6-diaryl-4-pyridinecarbinols (Structure 1, R =H, having R and R as lower alkyl groupings with (Ar) and (Ar) as substituted phenyl groups having at least one trifluoromethyl substituent is outlined in Chart 1 and Chart 3. The requisite products have Formula III. This method was applicable to types having (Ar); and (Ar) either the same or differing aryl functions. The intermediate oxirane could be caused to react with various primary amines (R =H; R =alkyl) or secondary amines (R and R each, being alkyl groupings, the same or different). Said carbinolamines (Formula III) were most satisfactorily administered in the form of acid-addition salts.

The requisite alpha-(2 piperidyl)-2,6-diaryl-4-pyridylcarbinols (Formula IV) were prepared from the intermediate 2,6-diaryl-isonicotinic acids (Formula II) in the manner outlined in Chart 2. As in the instance of the less complex carbinolamines (Chart 1), so also the products (Formula IV) of transformations given in Chart 2 were most conveniently used in the form of their acid-addition salts.

The examples hereinafter given further illustrate the preparation of 4-pyridylcarbinolamines of Formula I, but in no way limit the scope of the invention to Formulas III and IV as representative thereof. Said representations are not to be viewed as restricted to a single stereoisomeric form. All temperatures are given in degrees Celsius C.), and metric units are employed for weights and measures.

EXPERIMENTAL Synthetic paths leading to the examples have been shown in Charts 1, 2 and 3, and all are illustrative of the invention relating to 4-pyridylcarbino1amines having Formula 1. Alternative routes for acquiring certain intermediates are apparent to those skilled in the art, and certain of these are revealed in the examples. For convenience, the examples have been separated into sections to ensure clarity. Thus, the common intermediate 2,6-diaryl isonicotinic acids (Formula II) have been illustrated in Examples 1 through 6. Examples 7 through 27 are illustrative of the modes for synthesis of the carbinolamines of Formula III, and Example 27 relates to compound of Formula IV.

(A) TRIFLUOROMETHYL SUBSTITUTED-2,6- DIPHENYL ISONICOTINIC ACIDS Example 1.2,6-bis (4-trifiuoromethylphenyl) isonicotinic acid (1) 4-trifluoromethylphenacyl bromide.To a solution of 4-trifluoromethy1acetophenone (25 g., 0.13 mole) in chloroform (100 ml.) was added a solution of bromine (10.5 g., 0.13 mole) in chloroform (40 ml.). The reaction mixture was stirred at room temperature for 15 min. The chloroform solution was washed with water (x4), dried (Na SO and concentrated. The crude bromomethyl ketone was recrystallized from petroleum ether (B.P. 30 60) to yield the title compound (29.3 g., 83%), M.P. 5456.

Analysis.Ca1cd. for C H OF Br (percent): C, 40.48; H, 2.27; F, 21.34. Found (percent): C, 40.47; H, 2.33; F, 21.08.

'(2) N(4 trifluoromethylphenacyl)pyridinium bromide.A solution of the above bromoketone (28.3 g., 0.16 mole) in ethanol (70 ml.) containing pyridine (10 ml.) was refluxed for min. Ether was added to the cooled solution until turbid and the solution was allowed to stand overnight. Filtration afforded 32 g. (60%) of the title pyridinium salt, M.P. 219-221 (dec.).

Analysis.-Calcd. for C I-I NOF Br (percent): C, 48.58; H, 3.20; N, 4.05; F, 16.47. Found (percent): C, 48.59; H, 3.36; N, 4.28; F, 16.21.

(3) 3-(4-trifluoromethylbenzoyl)acrylic acid.-Freshly fused zinc chloride (82 g., 0.6 mole) was dissolved in dry ether (400 ml.) and added dropwise to the Grignard reagent prepared from p-bromobenzotrifluoride (112.5 g., 0.5 mole) and magnesium (12.2 g., 0.5 g. atom) in ether (600 ml.). To the above suspension, maleic anhydride (44 g., 0.45 mole) in ethereal solution (ca. 400 ml. of ether) was added over 30 min., with stirring and refluxing. Refluxing was continued for another 2 hr. The reaction mixture was cooled and acidified with 10% hydrochloric acid. The ethereal solution was separated, dried (magnesium sulfate) and the solvent evaporated. The dark residue was recrystallized several times from benzene until a sharp melting product was obtained, yield 24.5 g. (21% M.P. 149- 151.

Analysis.Calcd. for C H O F (percent): C, 54.11;

4 H, 2.89; F, 23.34. Found (percent): C, 54.14; H, 3.06; F, 23.60.

An alternative, improved method of preparation of 3- (4 trifluoromethylbenzoyl)-acrylic acid is as follows. 4- trifluoromethylacetophenone (376 g., 2 mol) and glyoxylic acid (376 g.) were heated at 7980 for 8 hr. The reaction mixture was poured in 4 l. of water containing 38 ml. of concentrated hydrochloric acid with stirring. The mixture was extracted with ether (3 1. x1; 1.5 1. x1). The ether extract was washed with water and the ether was removed under reduced pressure. The residue was azeotroped with chloroform (1 1.), then stirred with petroleum ether (2.8 1., B.P. 30-60"). The mixture was filtered and the solid was washed with petroleum ether. The solid was stirred wtih hot chloroform (600 ml.), cooled and filtered to yield 141 g. of 2-hydroxy-3-(4-trifluoromethylbenzoyl)propionic acid, 118'-119.5 C. The petroleum ether filtrate and washings were combined and the solvent was removed under reduced pressure to yield 205 g. of unreacted 4-trifluoromethylacetophenone. The yield of hydroxyacid, based on recovered starting material, was 59%. The hydroxyacid (262 g.) was heated in an oil bath at 155l60 for 40 min. to yield crude 4-trifluoromethy1benzoylacrylic acid. The crude product was used as such in the next reaction.

(4) 2,6-bis (4-trifluoromethylphenyl)isonicotinic acid. To a solution of 4.8 g. (0.02 mole) of 3-(4-trifluoromethylbenzoyl)acrylic acid in 50 ml. of methanol, there was added 7.0 g. 0.02 mole) of N-(4-trifluoromethylphenacyl) pyridinium bromide and 16 g. of ammonium acetate. The mixture was refluxed for 6 hr. Alternatively, the addition of acetic acid proved beneficial and the reflux time was reduced to 4 hr. by this variation. The solvent was removed in vacuo and the residue so obtained was treated with 20 ml. of hot 50% acetic acid, stirred for some while and cooled. The product was collected by filtration, washed with water, dried and then recrystallized from benzene. There was thus obtained 6.6 g. of the desired isonicotinic acid type, M.P. 285286.

Analysis.Calcd. for C H F NO (percent): C, 58.40; H, 2.70; N, 3.41. Found (percent): C, 58.65; H, 2.85; N, 3.50.

Example 2.2-(4-chloropheny1)-6-(4-trifluoromethylphenyl) isonicotinic acid The procedure described in Example 1 was employed for the interaction of N-(4-trifluoromethy1phenacyl)pyridinium bromide, 3-(4-chlorobenzoyl)acrylic acid, and ammonium acetate in methanol. The requisite product was obtained in 69% yield. The pure compound, obtained by crystallization from propanol-Z, had M.P. 269-271".

Analysis.-Ca1cd. for C H NO ClF (percent): C, 60.41; H, 2.94; N, 3.71; F, 15.09. Found (percent): C, 60.13; H, 3.20; N, 3.52; F, 15.10.

Example 3.--2- (4-bromophenyl -6- (4-trifluoromethylphenyl)isonicotinic acid The method given in Example 1 was followed. 3-(4- bromobenzoyl)acrylic acid, N-(4 trifluoromethylphenacyl)pyridinium bromide and ammonium acetate were refluxed in methanol solvent for five hours. After workup, the product was crystallized from acetic acid to give a 60% yield of the titled isonicotinic acid, M.P. 280-283".

Analysis.Calcd. for C H NO BrF (percent): C, 54.05; H, 2.63; N, 3.32; F, 13.50. Found (percent): C, 53.85; H, 2.76; N, 3.49; F, 13.25.

Example 4.2-(3,4-dich1orophenyl)-6-(3-trifluoromethylphenyl)isonicotinic acid (1) 3 trifluoromethylphenacyl bromide.3-trifluoromethylacetophenone (18.8 g.) was brominated (16 g. of bromine) in ml. of chloroform as described for Example 6. After the usual workup (cf. Example 1), there was obtained 21 g. (79% yield) of colorless oil which was used directly without purification.

(2) N (3 trifluromethylphenacyl)pyridinium bromide.-The requisite phenacyl bromide and pyridine were interacted in ethanol solution as described in Example 1. The crude quaternary salt was recrystallized from ethanol to give 85% of product, M.P. 248249.

Analysis.Calcd. for C H BrF NO (percent): C, 48.57; H, 3.20; N, 4.05. Found (percent): C, 48.49; H, 3.49; N, 3.96.

(3) 2 (3,4 dichlorophenyl) 6 (3-trifiuoromethylphenyl)isonicotinic acid.The foregoing quaternary ammonium salt was caused to react with 3-(3,4-dichlorobenzoyl)acrylic acid in the manner described in Example 1 to yield 80% of the title isonicotinic acid, M.P. 239- 240, after crystallization from ethanol.

Analysis.-Calcd. for C H Cl F O N (percent): C, 55.37; H, 2.43; N, 3.40. Found (percent): C, 55.34; H, 2.63; N, 3.37.

Example 5 .-2- 3 ,4-dichlorophenyl) -6- (4-trifluoromethylphenyl)isonicotinic acid The intermediate quaternary ammonium salt from Example 1 was caused to react with 3-(3,4-dichlorobenzoyl) acrylic acid after the manner described in Example 1. A 79% yield of product was obtained with M.P. 288-290", after crystallization from ethanol.

Analysis.-Calcd. for C H Cl F NO (percent): C, 55.37; H, 2.43; N, 3.40. Found (percent): C, 55.44; H, 2.63;N, 3.39.

Example 6.2,6-bis 3-trifluoromethylphenyl) isonicotinic acid (1) 3 (3 trifluoromethylbenzoyl)acrylic acid.-The title compound was prepared from 3-trifluoromethylacetophenone (20 g.) and glyoxylic acid hydrate (20' g., 80% purity) using the alternative procedure described for Example 1. The crude product was a mixture (8.5 g.) of hydroxy and acrylic acid (M.P. 85-115") and was used for the next step without purification.

(2) N (3 trifluoromethylphenacyl)pyridinium bromide.The title compound was prepared from u-bromom-trifluoromethylacetophenone (13.5 g.), pyridine (20 ml.) and ethanol (20 m1.) using the procedure described in Example 1. The product was recrystallized from ethanol and gave 14.6 g. (85%) of material, M.P. 248-249.

Analysis.Calcd. for C H BrF NO (percent): C, 48.57; H, 3.20; N, 4.05. Found (percent): C, 48.49; H, 3.49, N, 3.96.

(3) 2,6 bis(3 trifluoromethylphenyl)isonicotinic acid.The foregoing mixture of hydroxy and acrylic acids (8.5 g.), n- (3 trifluoromethylphenacyl)pyridinium bromide (11 g.) ammonium acetate (20 g.), and acetic acid (10 ml.) in methanol 100 ml.) were refluxed for 8 hours. The solution was evaporated to dryness and the residue was treated with hot 50% acetic acid (30 ml.). After stirring and cooling, the dark product was separated and crystallized from benzene (x2). The yield was 6.8 g. (51%), M.P. 219-220".

Analysis.Calcd. for C H F NO (percent): C, 58.40; H, 2.70. Found (percent): C, 58.62; H, 2.78.

(B) TARGET COMPOUNDS Example 7.-Alpha- (n-butylaminomethyl -2,6-bis (4- trifluoromethylphenyl -4-pyridinecarbino1 (1) Diazomethyl 2,6 bis(4-trifluoromethylphenyl)-4- pyridyl ketone.-The intermediate 2,6-bis(4-trifiuoromethyl)isonicotinic acid (5 g.) from Example 1 was dissolved in thionyl chloride (50 ml.) and refluxed for 3 hours. The solution was concentrated and the residue was suspended in benzene. The solvent was evaporated and the crude acid chloride was dissolved in dichloromethane (50 ml.) and added to a solution of diazomethane (ca. 5 g.) in ether (300 ml.) at 0". The reaction mixture was refrigerated overnight. The excess of diazomethane and ether was removed under reduced pressure. The crystalline diazoketone was suspended in' a mixture of ether-petroleum ether. The resulting precipitate was separated (4.2 g., 80%,

6 M.P. 152-165 and used directly in the next step. A sample for analysis was purified by crystallization from ether-petroleum ether, M.P. 165-166 (dec.).

Analysis.Ca1cd. for C H F N O (percent): C, 57.91; H, 2.55; N, 9.65. Found (percent): C, 57.81; H, 2.59; N, 9.80.

(2) Bromomethyl 2,6-di-p-trifluoromethylphenyl-4-pyridyl ketone.The above diazoketone (4 g.) was added in several portions to a mixture of 48% hydrobromic acid 10 ml.) in acetic acid ml.). The solution was stirred at room temperature for 1 hr. and diluted with cold water. The resulting precipitate was suspended in dilute sodium carbonate, filtered, washed with water and dried. The crude product was recrystallized from ethanol, M.P. 153- l54, yield 3.5 g. (77% Analysis.-Calcd. for C H F BrNO (percent): C, 51.66; H, 2.48; N, 2.87. Found (percent): C, 51.88; H, 2.48; N, 3.00.

3) Alpha (n butylaminomethyl)-2,6-bis(4-trifiuoromethylphenyl)-4-pyridinemethanol.-Epoxide: A solution of sodium borohydride mg.) in water (5 ml.) was added to a solution of the above bromoketone (1.7 g.) in hot ethanol (50 ml.). The solution was stirred at room temperature for 2 hr. Part of the ethanol was evaporated and the excess of borohydride was destroyed with 5% hydrochloric acid. The pH of the mixture was adjusted to 7 with aqueous sodium bicarbonate. The product was extracted with ether. The extract was washed with water, dried (K CO and the ether was evaporated to leave crude epoxide (1.2 g., 82%) which was used without further treatment.

Carbinolamine hydrochloride: The above crude epoxide (1.2 g.) was dissolved in ethanol (50 ml.), mono-nbutylamine (5 ml.) added and the solution refluxed for 18 hrs. The reaction mixture was evaporated to dryness, the residue dissolved in ether (ca. 600 ml.), washed with water, dried (K CO and concentrated (to ca. 10 ml.). After cooling, the colorless precipitate was separated (700 mg.), dissolved in hot ethanol and converted to the hydrochloride salt with 10% aqueous hydrochloric acid. After refrigeration overnight, the hydrochloride salt was separated, washed with water and recrystallized from a mixture of ethanol and ether. The yield was 700 mg. (40% M.P. 253-255.

Analysis.Calcd. for C H ClF N O (percent): C, 57.86; H, 4.86; N, 5.40. Found (percent): C, 57.56; H, 4.80; N, 5.31.

(4) Alternatively, the 2,6-bis-(4-trifluoromethylphenyl)isonicotinic acid may be converted to the target antimalarial compound, alpha-(n-butylaminomethyl-2,6-bis- (4-trifluoromethylphenyl)-4-pyridinecarbinol, by an alternative procedure which avoids the use of diazomethane, a hazardous reagent not suitable for large scale work. The sequence is shown in Chart 3.

The isonicotinic acid from Example 1 was refluxed in ethanol containing sulfuric acid to yield the ethyl ester M.P. 124.5-125.5, in 92% yield. This is Structure I of Chart 3. This is interacted with ethyl acetate in the presence of one equivalent of sodium ethoxide to obtain ethyl 2,6 bis (4 trifluoromethylphenyl)isonicotinoylacetate, M.P. 137-138, in 95% yield. This is Structure II of Chart 3. This was hydrolyzed and decarboxylated by refluxing the ketoester in a mixture of hydrochloric acid and acetic acid to form methyl 2,6-bis(4-trifluoromethylphenyl)-4-pyridyl ketone, M.P. 139-1405", in 97% yield. This is Structure III of Chart 3.

The foregoing ketone was brominated in acetic acid at 80-90 over a 30 min. period. The reaction mixture was cooled, poured into water and extracted with chloroform. The chloroform solution was washed with sodium bicarbonate and water and dried. The solution was concentrated and bromomethyl 2,6-bis-(4-trifluoromethylphenyl)-4-pyridyl ketone, M.P. 152-154, identical in all respects with the compound reported above, was isolated in 84% yield. This is Structure IV of Chart 3. The procedure to convert the bromoketone, to the antimalarial compound, alp'ha-(n butylaminomethyl) 2,6 bis-(4'-trifluoromethylpheny'l)4-pyridinecarbinol, is the same as that reported above.

Example 8 alpha l (n-p entylaminomethyl) -2,6-bis- 4-trifluoromethylphenyl) -4-pyridinecarbino1 The intermediate epoxide from Example 7 in ethanol solution was treated with n-pentylamine as described in Example 7. The resulting hydrochloride salt isolated was recrystallized from acetonitrile, M.P. 225 227, in 75% yield.

Analysis.Calcd. for cggHgqNzFscloIl (percent): C, 58.58; H, 5.11; N, 5.25; Cl, 6.65. Found (percent): C, 58.51; H, 5.31; N, 5.40; Cl, 6.95.

Example 9.Alpha- (n-hexylaminomethyl -2,6-bis- (4-trifiuorornethylphenyl) -4-pyridinecarbinol The intermediate epoxide described in Example 7 was treated with n-hexylamine as described in Example 7. The title compound was isolated in the form of its hydrochloride salt, M.P. 208-209, in a yield of 75%; following crystallization from acetonitrile.

Analysis.Calcd. for CgqHzgNzFeClO (percent): C, 59.27; H, 5.36; N, 5.12; Cl, 6.48. Found (percent): C, 59.00; H, 5.65; N, 5.22; CI, 6.75.

Example 10.-A1pha- (n-heptylaminomethyl -2,6-bis- (4- trifluoromethylphenyl) -4-pyridinecarbinol The intermediate epoxide from Example 7 was treated with n-heptylamine as described, in Example 7. A 71% yield of hydrochloride of the title compound, M.P. 198- 199 was obtained, following crystallization of the crude material from acetonitrile.

Analysis.Calcd. for C H N F ClO (percent): C, 59.94; H, 5.57; N, 4.99; CI, 6.32. Found (percent): C, 60.01; H, 5.77; N, 5.08; Cl, 6.54.

Example 11.-Alpha- (n-octylaminomethyl -2,6-bis- (4- trifluorornethylphenyl) -4-pyridinecarbino1 Example 12.Alpha-(cyclobutylaminomethyl)-2,6-bis(4- trifiuoromethylphenyl) -4-pyridinecarbinol A solution of the epoxide (0.9 g.) from Example 7, monocyclobutylamine (8 ml.) and ethanol (20 ml.) was refluxed for 18 hrs. The solution was evaporated to dryness. The solid free base was suspended in petroleum ether (20 ml.) and separated. The solid was then dissolved in ethanol (5 ml.) and acidified with hydrochloric acid. The solution was diluted with water (ca. 10 ml.) and the hydrochloride salt was filtered. The salt was recrystallized from acetonitrile to give 750 mg. (69%) of the product, M.P. 265-267.

Analysis. Calcd. for C H ClF N O (percent): C, 58.33; H, 4176; N, 5.63. Found (percent): C, 58.09; H, 4.49; N, 5.42.

Example 13.Alpha- (4-heptylaminomethyl -2,6-bis (4-trifluoromethylphenyl) -4-pyridinecarbinol The above compound was prepared from epoxide (0.9 g.) from Example 7 and 4-heptylamine (10 ml.) using the procedure described for Example 12. The yield was 70%, M.P. 202-204" (acetonitrile), of the hydrochloric salt. 1

Analysis.Calcd. for C H ClF NO (percent): C, 59.94; H, 5.57; N, 4.99. Found (percent): C, 60.22; H, 5.87; N, 5.12.

8 Example 14.Alpha- (ethylaminomethyl) -2-,6-l5is(4.-

trifiuoromethylphenyl)-4-pyridinecarbinol Example 15 .Alpha- 2-butylaminomethyl)-2,6-bis(4- trifluoromethylphenyl -4-pyridinecarbin0l The title compound was prepared from the epoxide (600 mg.) from Example 7 and sec.butylamine (8 ml.) using the standard procedure described in Example 12; The yield of hydrochloride salt was M.P. 242-245 (ethanol-ether).

Analysis.Calcd. for C H 'ClF N O (percent): C, 57.68; H, 4.86; N, 5.40. Found (percent): C, 57.68; H, 5.13; N, 5.61.

Example 16.-Alpha-( 1'-propylaminomethyl)-2,6- bis (4-trifiuoromethylphenyl) -4-pyridinecarbinol The title compound was prepared from the epoxide (600 mg.) from Example 7 and propylamine (8 ml.) using the procedure described in Example 12. The yield of hydrochloride salt was M.P. 267269 (ethanol-acetonitrile) Analysis.Calcd. for C H ClF N O (percent): C, 57.09; H, 4.59; N, 5.55. Found (percent): C, 56.89; H, 4.87; N, 5.73.

Example 17.Alpha-(cyclohexylaminomethyl)-2,6- bis(4-trifluoromethylphenyl)-4-pyridinecarbinol The title compound was prepared from the epoxide (1 g.) from Example 7 and cyclohexylamine (10 ml.) using the procedure described in Example 12. The product salt was crystallized from ethanol to give 700 mg. (62%) of colorless crystals, M.P. 266-268.

Analysis-Calcd. for CgqHgqClFgNgO (percent): C, 59.50; H, 4.99; N, 5.14. Found (percent): C, 59.21; H, 4.92; N, 5.27.

Example 18.Alpha- (di-n-butylaminomethyl) -2,6-bis (4-trifiuoromethylphenyl -4-pyridinecarbinol The epoxide from Example 7 (2.3. g.) was dissolved in ethanol ml.). Di-n-butyla'mine (10 ml.) was added and the solution was refluxed for 15 hrs. The reaction mixture was evaporated to dryness. Theresidue was dissolved in a small amount of ethanol and the solution was acidified with 10% hydrochloric acid. Crystalline title compound separated after standing at room temperature for several hours. The product was separated, washed with water, suspended in ether (to remove any epoxide), separated again and dried. The product was crystallized from a mixture of ethanol-water, yield 1.7 g. (52%), M.P. 233-235.

Analysis.Calcd. for C H ClF N O (percent): C, 60.57; H, 5.78; N, 4.87; C], 6.17. Found (percent): C, 60.63; H, 5.78; N, 4.83; Cl, 6.31.

The above alpha-(di n butylaminomethyl)-2,6-bis-(4- trifluoromethylphenyl)-4-pyridinecarbinol was resolved into its two optical antipodes in a conventional manner by conversion of the compound into the L(d)-tartarate salt. By fractional crystallization, there was obtained salts rich in dextrorotatory and laevorotatory antipodes. The antipodes were liberated from the L(d)-tartarate salts and converted back into the hydrochloride salts. As determined on a polarimeter, the rotations for the two antipodes as hydrochloride salts were [M +10.75, C. 2.1 ethanol and -10.68, C. 1.76 ethanol. The two antipodes melted at 239-240 and 236-237, respectively. The antimalarial activity of the two antipodes was difierent, the activity of each antipode was significantly different than that of the original racemic mixture. Y

An-"o-suec'inoyl derivativeof the title pyridinecarbinol wasprepared-. The hydrochloride salt was first converted to the free base by treatment with sodium hydroxide.

The free base (1 g.) was dissolved in 50 ml. of anhydrous acetoneIToihi's solutionwas added 210 mg. of succinic'anhydridq' then the solution was refluxed for 1 hour. Following evaporation of the solvent, the residue was suspended in'coldwater, then acidified to pH 4 with dilute hydrochloricacid. Following cooling, a crystalline solid separated,-and was crystallized from propanol-2. An 85% yield (990mg) of the o-succinoyl derivative was obtainedin the form of its hydrochloride salt. This compound melted'at 176-178.

Analysisr -calcd. for C H N' ClF O (percent): C, 58.71; H, 5.5 2; N, 4.15. Found (percent): C, 58.68; H, 5.80;"N,f4.26. i

Example 19. AIpha-(di n-pentylaminomethyl)-2,6-bis-(4- trifluoromethylphenyl) 4-.pyridinecarbinol lThe requisitelepoxide,(Example 7) and di-n-pentylamine were caused in interact in ethanol solution after the manner described Example 18. 'Ihe hydrochloride salt was formed, and then crystallized from ethanol-water. A yield of about 53%"resulted. The compound melted 225- 228- Analysis-Calcd. for 'C H ClF -N O (percent): C, 6.73; H,- 6.18; N, 4.65. Found (percent): C, 61.57; H, 6.19; N, 4.72. l

Example20. Alpha-(di-4-heptylaminomethyl)-2,6-bis(4- trifiuoromethylphenyl)-pyridinecarbinol hydrochloride "The title compound was prepared from the correspondirig epoxide (1 .5 g.) frbrnExarnple 7 and 4-diheptylamine ml.) in ethanol (50 ml.)- using-jthe procedure in Example 18. The product weighed 650 mg., MJP. 2112l3, after-crystallization' frdmiacetonitrile. The yield was 650 mg, M.P. 211-2137. a 1;

Analysis.Calcd. for C H ClF N O (percent): C, 63.77; H,"6';88;'N, "4:281Found (percent): C, 63.93; H, 7.06; N, 4:30. v

Example 21 Alpha (di n-butylaminomethyD-2-(4- I chlorophenyl) 6 (,4-trifluoromethylphenyl)-4-pyridine- "carbinol (1) Bromomethyl 2 i- (4 chlo'rophenyl)-6-(4-trifluoromethylphenyl)r-4-pyridyl ketone. The intermediate isonicotinicaci'd from Example 2 was converted into the acid chloride, which was thenusedin crude form for conversion into the diazomethyl ketone, also used without purification. The diazoketone and hydrobrpmic acid were caused to react in the presence of chloroform to obtain a 64% yield of the title bromomethyl ketone. This, following recrystallization 'frompropanol '2, was obtained in 64% yield, M.P. 124-127".

(2) Alpha (di-n-butylaminomethyl)-2-(4-chlorophenyl) 6-(4-trifluoromethylphenyl)-4-pyridinecarbinol.In the usual manner, the foregoingbromomethyl ketone was convertedfinto the epoxideand treated with di-n-butylamine and gave a 34% yield of the hydrochloride of the requisite carbinolamine, M.P. 229-231 following crystallization from propanol-2.

for C2 H33Cl2F3N2O (percent): C, 62.11; H, 6.14; N, 5.17; Cl, 13.10; F, 10.53. Found (percent): C, 61.99; I -I, 6.39; N, 5.26;;Cl, 13.15;'F, 10.59.

Example H 22. -Al pha; (n-butylaminomethyl) -2- (4-b romophenyl) -6- 4-trifluorom'ethylphenyl 4-pyridinecarbinol (1) Bromomethyl 2-(4-bromophenyl)-6=(trifluoromethyl)-4-pyridyl ketone.-The required intermediate isonicotinic acid from Example 3. ,was, coi1verted into its acid chloride, which melted at 139-l41 following crystallization from benzene. The yield Was- 81%. By analysis, the compound contained 12.72% fluorine vs. 12.83% calculated. This acid chloride was interacted with diazomethane and then reacted with hydrobromic acid. There resulted thereby a 68% yield of the required bromomethyl ketone of M.P. 136-138 (from propanol-2).

Analysis.-Calcd. for C H Br F NO (percent): C, 48.05; H, 2.58; N, 2.80; F, 11.40. Found (percent): C, 48.13; H, 2.69; N, 3.00; F, 11.68.

(2) Alpha (n-butylaminomethyl)-2-(4-bromophenyl)- 6 (4 trifiuoromethylphenyl)-4-pyridinecarbinol.The foregoing bromoketone was reduced with sodium borohydried in ethylene glycol monoethyl ether, to obtain the crude, intermediate epoxide which was interacted with nbutylarnine in ethanol solution. The free base was obtained as a nicely crystalline solid from propanol-2 and melted l57158.5. The yield was 49%.

Analysis.Calcd. for C H N BrF O (percent): C, 58.43; H, 4.90; N, 5.68; F, 11.55. Found (percent): C, 58.27; H, 4.85; N, 5.51; F, 11.22.

Example 23 .Alphadi-n-butylaminomethyl -2- (4-bromophenyl) 6 (4-trifluoromethylphenyl)-4-pyridinecarbinol The crude epoxide obtained according to Example 22 was interacted with di-n-butylamine in ethanol solution to obtain a crude base, which was transformed into its hydrochloride salt. This salt was obtained in 40% yield, and melted 229-231 (crystallization effected from propanol-2).

Analysis.-Calcd. for. C H BrClF NO (percent): C, 57.39; H, 5.68; N, 4.78, F, 9.73. Found (percent): C, 57.16; H, 5.93; N, 4.85; F, 10.04.

Example 24.Alphadi-n-butylarninomethyl -2- 3 ,4-dichlorophenyl)-6-(3 trifiuoromethylphenyl)-4-pyridinecarbinol The intermediate isonicotinic acid derivative prepared according to Example 4 was converted to crude acid chloride which was converted in turn to the diazomethyl ketone by interaction with diazomethane. The crude diazomethyl ketone was obtained in 82% yield. The bromomethyl ketone was obtained in 89% yield from the diazomethyl ketone by interaction with hydrobromic acid. Reduction of the bromomethyl ketone with sodium borohydride in the usual way gave the intermediate epoxide of adequate purity for direct conversion into the required compound. The yield so obtained was 35%. The hydrochloride was crystallized from propanol 2, and then melted 178-179.

Analysis.Calcd. for C H Cl F N O (percent): C, 58.39; H, 5.60; N, 4.86. Found (percent): C, 58.12; H, 5.80; N, 4.78.

Example 25.-Alpha-(di-n-butylaminomethyl)-2-(3,4-dichlorophenyl) 6 (4-trifluoromethylphenyl)-4-pyridinecarbinol The requisite isonicotinic acid starting material was obtained after the procedure of Example 5, then converted successively, into the acid chloride, the diazomethyl ketone, and the bromomethyl ketone, and thence into the epoxide for interaction with di-n-butylamine. The yields in the first several steps were in excess of however, the conversion of the bromoketone into the finished product was about 40%. The hydrochloride of the desired compound melted 208-210 following crystallization from acetonitrile and water.

Analysis.Calcd. for C H CI F N O (percent): C, 58.39; H, 5.60; N, 4.86. Found (percent): C, 58.18; H, 5.80; N, 4.72.

Example 26.-Alpha-(n-butylaminomethyl)-2,6-bis- (3-trifiuoromethylphenyl -4-pyridinecarbinol (1) Diazomethyl 2,6 bis-(3-trifluoromethylphenyl)-4- pyridyl ketone.The isonicotinic acid (4.5 g.) from Example 6 was dissolved in thionyl chloride (50 ml.) and the mixture was refluxed for 3 hours. The solution was concentrated. The residue was suspended in benzene and the solvent was evaporated. The crude acid chloride was dissolved in dichloromethane (50 ml.) and added to a solution of diazomethane (5 g.) in ether (300 ml.) at After refrigeration overnight, the solvent and the excess of diazomethane were evaporated. The crude diazoketone (4.2 g.) solidified at 6", but was liquid (oil) at room temperature. It was used for the next step without purification.

(2) Bromomethyl 2.6-bis-(3-trifluoromethylphenyl)-4- pyridyl ketone.-The above diazoketone (4.2 g.) was dis solved in dichloromethane (50 ml.) and added to a mixture of 48% hydrobromic acid (10 ml.), acetic acid (20 ml.) and dichloromethane (100 ml.). The solution was stirred at room temperature for one hour and diluted with cold water. The solvent layer was separated. The Water layer was extracted with more dichloromethane (100 ml.) and the combined extracts were washed with dilute sodium bicarbonate solution. After drying the solvent was evaporated and the semisolid residue was crystallized from ethanol. The yield was 2.6 g. (56%), MP. 75-77.

Analysis.Calcd. for C H F BrNo (percent): C, 51.66; H, 2.48; N, 2.87. Found (percent): C, 51.86; H, 2.70; N, 3.05.

(3) Alpha-(n-butylaminomethyl) 2,6 bis(3-trifluoromethylphenyl) 4 pyridinecarbinol hydrochloride.A solution of sodium borohydride (300 mg.) in water (5 ml.) was added to a solution of the above bromoketone (2.2 g.) in ethanol (60 ml.) as described in Example 7. The resulting crude epoxide (1.5 g.) was dissolved in ethanol (50 ml.). n-Butylamine ml.) was added and the solution refluxed for 10 hours. The reaction mixture was evaporated to dryness and the crude product converted to the hydrochloride as described in Example 7. It was crystallized from a mixture of ethanol-ether to give 750 mg. (32%) of colorless crystals, M.P. 256258.

Analysis.Calcd. for C H ClF -N O (percent): C, 57.86; H, 4.86; N, 5.40. Found (percent): C, 57.77; H, 4.81; N, 5.42.

Example 27.Alpha- (2-piperidyl -2,6-bis- (4- trifluoromethylphenyl )-4-pyridinecarbinol (l) 2,6-bis-(4-trifluoromethylphenyl)-4-pyridyl 2-pyridyl ketone.The solution of 2-bromopyridine (14.3 g., 0.08 mol) in ether (20 m.) was added to a solution of n-butyllithium in hexane (1.6 M, 56 ml., 0.1 mol) in anhydrous diethyl ether (120 ml.) at 70. The solution was stirred at '-70 for 1 hr. after which time 2,6-di-p trifluoromethylphenylisonicotinic acid (16.5 g., 0.04 mol) was added. The solution was stirred at 60 to '70 for 2 hrs. The reaction mixture was then allowed to warm to ca. 10 and poured into ice-water (750 ml.). The mixture was then extracted with ether (2X 400 ml.). The organic layer was dried and concentrated to dryness under reduced pressure. The resulting crude solid was crystallized from isopropyl alcohol to yield the title compound (12.4 g., 66%), MP. 143-145".

Analysis.Calcd. for C H N F O (percent): N, 5.93; F, 24.13. Found (percent): N, 5.72; F, 23.77.

(2) Alpha-(2-piperidyl) 2,6-bis-(4 trifluoromethylphenyl)-4-pyridinecahbinol.-Racemate A, free base: 2,6- di-(p-trifiuoromethylphenyl)-4-pyridyl ketone (4.6 g., 9.6 moles) was hydrogenated over platinum from platinum oxide (300 mg.) in ethanol (300 ml.) containing concentrated hydrochloric acid (1.1 ml.) at room temperature and 40 p.s.i. for hr.; the theoretical amount of hydrogen was absorbed. The catalyst was filtered and the filtrate was concentrated to dryness under reduced pressure. The hydrochloride salt was converted to the free base by shaking with potassium hydroxide (20%) and chloroform. The organic layer was dried and concentrated. The resulting solid was slurried in diethyl ether (80 ml.) and filtered to afford a solid (1.6 g.), M.P. 1 68-170; this was predominantly Racemate A by tlc (silica gel,

1'2 CHCl /MeOH, 6/ 1, R 0.28). This material was recrystallized from isopropanol jtoafiord pure Racemate A (1.1 g.), M.P. 168-170", one spot on tlc in thesame system. The yield was 24%. g Alnalysis.'Calcd. for C H N F O" (percent); C, 62.50; H, 4.62; N, 5.83; F, 23.72. Found (percent): C,- 62.55; H, 4.75; N, 5.63; F,'23.83 Racemate A, hydrochloride saltzRacemate A (1.1 g.) free base, was slurried in hot' isopropanol and isopropanol-HCl was added; the solid dissolved and. crystallized slowly. The solid was'collectedand recrystallized from isopropanol (x1) andjethanol-waterQc-l) to aiford pure Racemate A, hydrochloride salt (0.45 g.), MP. 248-2509. This product was shown v.by. elemental analysis to be a /2 hydrate. Yield was 59%. I I

A(nalysis.-Calcd. for C H N O F Cl (percent): C, 57.10; H, 4.60; N, 5.33. Found (percent): C, 56.80; H, 4.78; N, 5.27. A sample of this salt was converted to its free base and shown to be one spot (CHCl /MeOH, 6/ 1, R; 0.28). I. Y

Racemate B, hydrochloride salt: The ethereal filtrate from the isolation of Racemate-A was concentrated to dryness. The solid was slurried again in ether (20 ml.) and filtered to remove more Racemate A. To the filtrate was added ether-HCl. Water was then added to convert any dihydrochloride salt to the monohydrochloride salt. The ether was removed under reduced pressure and the aqueous slurry wasfiltered to yield a yellowish solid. The latter was slurried in ether to 'removet he yellow color and filtered to afford a white solid (0.5 g.)'. This solid was crystallized from isopropanol (x2):=to afford pure Racemate B, hydrochloridesalt (0.24 g.),-MP. 259 260. Elemental analysis showed the salt to be a V2 hydrate. w Y Analysis.-=Calcd. for C H N O F C1:(percent): C, 57.10; H, 4.60; N, 5.33. Found (percent): 6,157.44; H, 4.83; N, 5.28. g A sample of the hydrochloride salt-was. converted to its free base for tlc purposes and Was shown to beone spot (CHCl /MeOH, 6 /1, R 0.36). H

A mixture melting point of Racemates A and B, hydrochloride salts, was taken and the sample meltedat 227- 240.

'Y -CHARTY1" Alpha-(dialkylaminomethyl) 2,6-di ary1 4."" 7' pyridinecarbinols I I j An oo'oneo noozn. 3 Amcocme (IJOCHNa 14 I wherein one or (Ar) or (Ar) is 3 or 4-trifluoromethyl- 4 pyridinecarbinol.Exarnple 7 (also applicable to phenyl and the other is X-phenyl wherein X is selected Examples 8 to 20 inclusive) from trifluoromethyl and monoor difluoro, chloro or hromo groups wherein X is in the 3, 4 or 3 and 4 posi- O OH o OCZH tions and wherein in CF; is in the 3 or 4 position. 5

CHART 2 I I Alpha-(2-piperidyl)-2,6-diaryl-4-pyridylcarbinols CIHIOH Na, C2H5OH H 804 CHQCOZCZH: 2 10 N/ k \N/ (Am I 92 0 CHzCOzCzHs (I; CHJ

c0211 00 \N Br \N H01]: 0 Ac Br:

n-BuLi I HzPtOz M (Ar) (Am -60 H01 11 (957) N N 0 (Am Ar): m A]:

CH2BI 2% CH3 CH1 NaBH; n-C4H NHg A} HO-CH E /CH2 n xN/ (Al-)0 g HO(IJHCHzNH-I1-C4H (Ar). N (Am IV \N/ (Am The amine can be primary or secondary in place of wherein (Ar),; and (Ar) are as in Chart 1. gf and Wherem (Anz and (AUG are as in art CHART 3 The following Table I illustrates the antimalarial activity of the compounds of the present invention set forth Alternative procedure for the preparation of alpha-(di-nin Examples 7 to 27. The compounds are distinguished butylaminomethyl)-2,6-bis(4 trifluoromethylpheny1)- in that they produce cures in mice against P. berghez'.

TAB LE P. berghei screening test (mice) Phototoxicity Activity A MST; test (mice) b dose levels (mg/kg.) Cures, mgJkg. MED; mg./kg.

Patent appln. example number 20 40 320 640 I.p. Oral 27 Racemate A (tree base) 27 Racemate A 27 Raeemate B a Test method described by T. S. Osdene, P. B. Russell, and L. Rane, J. Med. Chem., 10, 431 (1967). This test has been made as a highly standardized procedure in which the P. berghei causes death of control mice at essentially 6.2 days. A11 increase in survival of mice by more than 2.5 days beyond this time has been found to be statistically significant. Mice which live more than 60 days are regarded as cured (C). Drugs which prolong the life oithdergfice beyond 14 days are considered active (A). Groups of five mice have been used at each dose evel of t e gs.

* Phototoxicity determined in mice by the method of W. E. Rothe and D. P. Jaeobus, J. Med. Chem, 11,

1 5 We: claim: I 1. The compound of the formula:

(IJOOH C Fa wherein X is selected from trifluoromet hyl and monoor 2. The compound of claim 1 wherein X isCF wherein CF;;- is in the 4-position. 3. The compound of claim 1 wherein XIis CF -Land wherein CF is inthe 3-position. 5

' References Cited UNITED STATES PATENTS 3,600,396 8/1971 Ash et a1. "260 296 R 10 ALAN L. ROTMAN, Primary Examiner U.S. c1. X.R.

di-fluoro, chloro or bromo groups, wherein X is in the 260293.69, 294.8 R, 295 H, 295 S, 296 R, 297 R; 3, 4 or 3 and 4 positions and wherein CF is in the 15 266 l 3 or 4 position.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 7 3 143 Dated October 2m1973 Arthur B. Ash, Peter Blumbergs, Anica Markovac and Invent0r(s) Maurice P. LaMontagne It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 47, "apha" should be --alpha-.

Column 2, line 4, "subsituted"shou1d be --substituted--.

Column 2, line 42, "R should be -It--.

Column 4, line 41', "c, 58.65" should be --c, 58. 56--.

Column 8, line 28, delete secondpercent sign.

Column 9, line 26, "6,73" should be --61. 73--.

Column 9, line 68, "trifluoromethyl" should be --trifluoromethylpheny1- Column 10, line 58, "80" should be --so%--.

H Y Column 10, lme 63, C H Cl F N O should be --C H Cl F N O Column 11, line 46, "(20 m. should be --(20 ml.

Column 13 line 1, "'or" (first instance) should be --of--. Table 1, insert "1? after Table.

Table 1, insert --5C-- under 640 for 27 Racemate A (free base).

FORM PO-lOSO (IO-69) USCOMM-DC 60376-P69 u.5. GOVERNMENT PRINTING OFFICE: 1969 o3es-s:u

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,763, 148 Dated October 2, 1973 Arthur B. Ash, Peter Blumbergs, Anica. Markovac and Inventor(s) Maurice P. LaMontagne v Page -2- It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Chart 1, line 53 "HH "Shou1d be NH Chart 3, line 15, the structure methyl 2, 6-bis(4-trifluoromethylphenyl)- 4-pyridyl ketone should be labeled --III-- under the structure.

Chart 3, line 25, the structure bromomethyl 2, 6-bis-(4-trifluoromethylphenyl)-4-pyridy1 ketone should be labeled -III( a.)-- under the structure.

Signed and sealed this 17th day of September 197 SEAL) Attest:

McCOY M. GIBSON, JR. C. MARSHALL DANN Attesting Officer Commissioner of Patents uscoMM-oc scan-P09 U. S. GOVERNMENT PRINTING OFFICE; i". l-I

i; "Otaivi F")-105O (10-69) 

